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    • Structure-guided Synthesis of Tamoxifen Analogs with Improved Selectivity for the Orphan ERRγ

    EYH Chao,JL Collins, S Gaillard,AB Miller,LP Wang, LA Orband-Miller,RT Nolte,DP McDonnell,TM Willson,WJ Zuercher

    Bioorganic & Medicinal Chemistry Letters（2006）SCI 4区SCI 2区

    Discovery Research | Department of Pharmacology and Cancer Biology | GlaxoSmithKline Inc

    Cited 102|Views36
    Abstract
    The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERR gamma LBD confirms the molecular basis of the selectivity. (c) 2005 Elsevier Ltd. All rights reserved.
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    ERR gamma,chemical tool,orphan nuclear receptor
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    【要点】：本文报道了通过结构导向合成的具有提高孤儿雌激素相关受体γ（ERRγ）选择性的他莫昔芬类似物，揭示了其分子选择性基础。
    

    【方法】：研究采用计算机辅助设计结合有机合成方法，设计并合成了一系列4-羟基他莫昔芬（4-OHT）衍生物。
    

    【实验】：通过测定这些衍生物与ERRγ和经典雌激素受体α的结合亲和力，发现带有羟基烷基团的类似物显示出比4-OHT更好的选择性结合谱。使用X射线晶体学方法确定了一个设计化合物与ERRγ结合的晶体结构，验证了选择性的分子基础。实验中具体使用的数据集未在摘要中提及。
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